PDBsum entry: 1k0u

Hydrolase

PDB id: 1k0u

Contents

Protein chains

(+ 2 more) 430 a.a. *

Ligands

NAD ×8

DEA ×8

Waters ×474

* Residue conservation analysis

PDB id:

1k0u

Name:

Hydrolase

Title:

Inhibition of s-adenosylhomocysteine hydrolase by "acyclic sugar" adenosine analogue d-eritadenine

Structure:

S-adenosyl-l-homocysteine hydrolase. Chain: a, b, c, d, e, f, g, h. Synonym: adenosylhomocysteinase. Engineered: yes

Source:

Rattus norvegicus. Norway rat. Organism_taxid: 10116. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Tetramer (from PQS)

Resolution:

3.00Å R-factor: 0.183 R-free: 0.265

Authors:

F.Takusagawa,Y.Huang,J.Komoto,Y.Takata,T.Gomi,H.Ogawa, M.Fujioka,D.Powell

Key ref:

Y.Huang et al. (2002). Inhibition of S-adenosylhomocysteine hydrolase by acyclic sugar adenosine analogue D-eritadenine. Crystal structure of S-adenosylhomocysteine hydrolase complexed with D-eritadenine. J Biol Chem, 277, 7477-7482. PubMed id: 11741948 DOI: 10.1074/jbc.M109187200

Date:

20-Sep-01 Release date: 17-Oct-01

Supersedes:

1d4g

Protein chains

P10760  (SAHH_RAT) -  Adenosylhomocysteinase

Seq: 432 a.a.

Struc: 430 a.a.

Enzyme reactions

• Enzyme class: E.C.3.3.1.1 - Adenosylhomocysteinase.
• Pathway: Adenosylhomocysteinase
• Reaction: S-adenosyl-L-homocysteine + H₂O = L-homocysteine + adenosine

S-adenosyl-L-homocysteine + H(2)O = L-homocysteine + adenosine (Bound ligand (Het Group name = DEA) matches with 85.00% similarity)

• Cofactor: NAD(+)

NAD(+) (Bound ligand (Het Group name = NAD) corresponds exactly)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 Gene Ontology (GO) functional annotation 

• Cellular component: cytoplasm (5 terms)
• Biological process: metabolic process (7 terms)
• Biochemical function: catalytic activity (7 terms)

reference

DOI no: 10.1074/jbc.M109187200

J Biol Chem 277:7477-7482 (2002)

PubMed id: 11741948

Inhibition of S-adenosylhomocysteine hydrolase by acyclic sugar adenosine analogue D-eritadenine. Crystal structure of S-adenosylhomocysteine hydrolase complexed with D-eritadenine.

Y.Huang, J.Komoto, Y.Takata, D.R.Powell, T.Gomi, H.Ogawa, M.Fujioka, F.Takusagawa.

ABSTRACT

D-eritadenine (DEA) is a potent inhibitor (IC(50) = 7 nm) of S-adenosyl-l-homocysteine hydrolase (AdoHcyase). Unlike cyclic sugar Ado analogue inhibitors, including mechanism-based inhibitors, DEA is an acyclic sugar Ado analogue, and the C2' and C3' have opposite chirality to those of the cyclic sugar Ado inhibitors. Crystal structures of DEA alone and in complex with AdoHcyase have been determined to elucidate the DEA binding scheme to AdoHcyase. The DEA-complexed structure has been analyzed by comparing it with two structures of AdoHcyase complexed with cyclic sugar Ado analogues. The DEA-complexed structure has a closed conformation, and the DEA is located near the bound NAD(+). However, a UV absorption measurement shows that DEA is not oxidized by the bound NAD(+), indicating that the open-closed conformational change of AdoHcyase is due to the substrate/inhibitor binding, not the oxidation state of the bound NAD. The adenine ring of DEA is recognized by four essential hydrogen bonds as observed in the cyclic sugar Ado complexes. The hydrogen bond network around the acyclic sugar moiety indicates that DEA is more tightly connected to the protein than the cyclic sugar Ado analogues. The C3'-H of DEA is pointed toward C4 of the bound NAD(+) (C3'...C4 = 3.7 A), suggesting some interaction between DEA and NAD(+). By placing DEA into the active site of the open structure, the major forces to stabilize the closed conformation of AdoHcyase are identified as the hydrogen bonds between the backbone of His-352 and the adenine ring, and the C3'-H...C4 interaction. DEA has been believed to be an inactivator of AdoHcyase, but this study indicates that DEA is a reversible inhibitor. On the basis of the complexed structure, selective inhibitors of AdoHcyase have been designed.

Selected figure(s)

Figure 1.
Fig. 1. Molecular structures of DEA found in the crystal (A) and in the rWT:DEA structure (B).

Figure 3.
Fig. 3. Schematic diagrams of interactions of DEA in the active site of rWT:DEA (A), and Ado* in the active site of rD244E:Ado* (B). Dashed lines indicate the possible hydrogen bonds and interactions.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2002, 277, 7477-7482) copyright 2002.

Figures were selected by an automated process.